Process for preparing distjbstituted



Patented Jan. 9, 1934 UNITED STATES PATENT QFFM'ZE PROCESS FOR PREPARING DISUBSTITUTED TETRAZOLES Georg Scheuing and Bruno Walach, Nieder- Ingelheim-on-the-Rhine, Germany, assignors, by mesne assignments, to E. Bilhuber, Incorporated, Jersey City, N. J a corporation of New Jersey No Drawing. Application April 5, 1929, Serial No. 352,905, and in Germany April 18, 1928 11 Claims.

Such esters are obtained in either of two ways. The first method is to bring esters of oximes to a temperature at which intramolecular rearrangement to the enolic ester of the corresponding mono-substituted acid amide takes place. This rearrangement occurs in a manner which is known per se according to the following formula:

The second method is to subject oximes to the action of acylating and enolizing agents, as for example PO15, P0013, S0012, CsH5.SO2Cl, CH3.C6H4.SO2C1, etc., by means of which the oxime esters, while being formed, undergo the said intramolecular rearrangement so that the resulting esters appear in the enolic form as esters of mono-substituted acid amides, or, as an alternative procedure, to esterify mono-substituted acid amides with the said acylating substances in the presence, or in the absence, of basic substances such as for instance pyridine, potassium carbonate or the like. The formation of the hydrazidines takes place according to the cquation:-

Starting from the oximes:

Starting from the acid amides:

The hydrazidines thus obtained may be converted in a manner known per se into tetrazoles by means of a further treatment with compounds containing and yielding the nitrous acid radical under the conditions of the process according to the following equation:-

The enol esters of the mono-substituted acid amides serving as starting materials need not be employed in a pure isolated form but can be used in the form in which they result in the reaction mixture, for example in the intramolecular rearrangement of oxime esters or in the esterii'lcation and enolization of mono-substituted acid amides.

Since the free hydrazidines are unstable and difficult to handle as well as the enol esters of the monosubstituted acid amides it is in general advisable to avoid isolating them and to carry out the conversion in one step according to the Equations 2 to 4 by starting with oximes or oxime esters or from mono-substituted acid amides or their esters.

As starting materials for the di-substituted tetrazoles are employed the esters of the enolic form of the mono-substituted acid amides such as are obtained from oximes or its esters or monosubstituted acid amides, in which the radicles R1 and R2 are represented by radicals of the group consisting of, the phenyl radical and any saturated aliphatic radicals, and methylene radicals cyclically connected together by three additional methylene radicals to the pentamethylene ring, such as e-lfillClIlB lactam or its esters. Of the esters of the above-mentioned compounds, the sulphonic acid esters, for example the tolueneor benzene sulphonic acid ester, of the cyclohexanone oxime or their transformation products, have in many cases proved to be especially suitable.

When employing oxime esters the process is carried out, for example, by treating the esters dissolved or suspended in a suitable organic solvent, for example benzene, with a solution of the hydrazine or hydrazine salt, for example the acetate, in a suitable solvent, for example alcohol, at ordinary temperature, then bringing the mixture to a temperature at which the intra-molecular rearrangement according to Formula 1 takes place, and then bringing and maintaining the mixture at the optimal reaction temperature for the formation of the hydrazidine until the formation of the hydrazidine has been entirely completed, for example by employing suitable cooling agents, the temperatures to be maintained from case to case depending on the kind of ester employed. Or in another way one may introduce the solution of the oxime ester in the solution or suspension of the hydrazine or hydrazine salt, maintained at the temperature the most convenient for the rearrangement and for the formation of the hydrazidine.

The agent for introducing the nitroso group, for example sodium nitrite and a mineral acid, is then added on cooling if desired and the tetrazole formed, separated in a suitable manner from the solution, for example by the addition of alkali until the solution reacts alkaline to phenolphthalein, evaporating and taking up the residue with chloroform.

Or starting from oximes the latter may be acylated by substances such as for example PO15 undergoing at the same time the intra-molecular conversion. The reaction mixture may be treated with hydrazine or a hydrazine salt and nitrous acid in statu nascendi in the above described manner.

When employing mono-substituted acid amides these may be subjected to the action of acylating agents such as for example acid halogenides such as benzeneor toluene sulpho-chlorides, in the presence of the alkaline reacting agents, preferably pyridine, in the presence of inert solvents such as for example chloroform, the hydrazine or hydrazine salt, for example hydrazine acetate, being allowed to react on the reaction product so obtained.

The present process offers inter alia the advantage over the known processes for preparing tetrazoles by m ans of free hydrazoic acid, of avoiding the use of hydrazoic acid, which is difiicult to handle and dangerous owing to its poisonous as well as to its explosive qualities. Compared with the known processes starting with. imido chlorides it ofiers the advantage of avoiding the substituted imido chlorides which particularly in the aliphatic and hydroaromatic series are with difliculty accessible and moreover unstable.

The following examples serve to illustrate how the invention may be carried into effect:-

(1) 100 grms. of p-toluene sulphonic acid ester of cyclo-hexanone oxime are dissolved in 200 cc. of benzene in the cold. A concentrated alcoholic solution of hydrazine acetate (110% of theory) is then added and the mixture carefully warmed to 30-35 C. This temperature is maintained by suitable cooling until the temperature no more spontaneously rises. The resulting solution of hydrazidine is treated with a cold saturated aqueous solution of 28 grms. of sodium nitrite. After the reaction is complete the solution is acidulated with a mineral acid to congo, evaporated and the residue taken up with chloroform.

1.5 pentamethylene-1-2-3-4-tetrazole of melting point 59 C. and boiling point of 192 C. (under 10 mm. pressure) is obtained in a yield of of theory and more.

The reaction is believed to be as follows:

(2) 113 grms. of e-leucine lactam (1 mol) are esterified with 1'77 grms. of benzene sulphonic chloride at 0 C. in the presence of chloroform and 1.2 mols of pyridine and the resulting solution of the enol ester is introduced into an alcoholic solution of hydrazine acetate (1.2 mol). The mixture is treated with sodium nitrite solution as in Example 1 and the resulting 1.5 pentamethylene 1-2-3-4-tetrazole is isolated in a similar manner.

(3) 36 grms. of methyl-acetamide are dissolved in 200 cc. of chloroform with the addition of grms. of pyridine and treated whilst cooling with 104 grms. of phosphorus pentachloride. After the conversion has taken place the solution containing the enol ester is introduced with stirring into a concentrated alcoholic solution of hydrazine acetate and then the hydrazidine in the solution treated with a cold saturated aqueous solution of sodium nitrite. A yield of about 40% of theory of 1.5 dimethyltetrazole (melting point 70-'71 C.) is obtained. The isolation is effected in a manner similar to that described in Example 1 for pentamethylene tetrazole.

The reaction is believed to be as follows:

(4) 34 grms. of acetanilide are dissolved in a mixture of 44 grms. of pyridine and 300 cc. of chloroform. 44 grms. of benzene sulphonic chloride are introduced drop by drop under vigorous stirring at a temperature of 20-25 C. After standing for a short time the crude solution of the enol ester is introduced drop by drop at a temperature of 20-25 0., into a solution of 8.5 grms. of hydrazine in a mixture of 100 cc. of methyl alcohol in 16 cc. of glacial acetic acid. The reaction mixture is allowed to stand for some time and is then treated with aqueous sodium nitrite solution. The 1-phenyl-5-methyl-tetrazole (melting point 99-100 C.) obtained may be separated from the reaction mixture as in the previous examples. This reaction is believed to be as follows:

The words acylating and enolizing agents in the specification and the claims are to be understood to include such substances which like inorganic acid halogenides for example P015, POCls, SOClz or organic acid halogenides, as for example benzeneor toluenesulfonyl chlorides or the like, which are adapted to esterify oximes or mono-substituted acid amides and to convert the esters formed by intra-molecular transformation into esters of the enolic form of monosubstituted acid amides.

The word hydrazine in the specification and the claims is to be understood to include not only free hydrazine but also hydrazine in salt form for example in the form of acetate.

The phrase, the compounds containing and yielding the nitrous acid radical, in the specification and in the claims is to be understood to include any compounds yielding nitrous acid in statu nascendi under the conditions of the process,

as for example, nitrous acid salts, particularly sodium nitrite, in the presence of or with addition of an acid.

What we claim is:

1. The process of preparing tetrazoles which comprises treating with a hydrazine a compound having the structure wherein Ac is a monovalent radical selected from the group consisting of -PC14, SOC1, POC12,

B" respectively represent a radical selected from the group consisting of the phenyl radical and any saturated aliphatic radicals, and methylene radicals cyclically connected together by three further methylene radicals to the pentamethylene ring, and then treating the hydrazidine thus formed with a compound containing and yielding the nitrous acid radical under the conditions of the process.

2. The process of preparing tetrazoles which comprises treating with a hydrazine a compound having the structure COAc wherein Ac is a monovalent radical selected from the group consisting of -PCl4, SOC1, POCl2, -SO2C6H5 and SO2C6H4-CH3 and R and B" respectively represent a radical selected from the group consisting of the phenyl radical and any saturated aliphatic radicals, and methylene radicals, cyclically connected together by three further methylene radicals to the pentamethylene ring, and then treating the hydrazidine thus formed with an alkali metal salt of the nitrous acid.

3. The process of preparing tetrazoles which comprises treating with a hydrazine a compound having the structure wherein Ac is a monovalent radical selected from the group consisting of PC14, --SOC1, POC12, SO2-C6H5 and SO2-C6H4-CH3 and then treating the hydrazidine thus formed with a compound containing and yielding the nitrous acid radical under the conditions of the process.

4. The process of preparing tetrazoles which comprises treating a non-enolized acid amide of the type:

it-H (wherein R and R" respectively represent a radical selected from the group consisting of the phenyl radical and any saturated aliphatic radicals, and methylene radicals cyclically connected together by three further methylene radicals to the pentamethylene ring) with an acylating and enolizing agent of the group consisting of P015, POCls, SOClz, CsHsSOzCl and CH3.C6H4.SO2C1 to form an enolic ester of the type R-COAc wherein Ac is a monovalent radical selected from the group consisting of PC14, SOC1, POC12,

SO2C6H5 and SOzCsI-I4CH3, treating the enolic ester thus formed with a hydrazine to form a hydrazidine and treating the latter with a compound containing and yielding the nitrous acid radical under the conditions of the process.

5. The process of preparing tetrazoles which comprises treating in the presence of a basic substance a non-enolized acid amide of the type: R([3=O R"NH (wherein R and B" respectively represent a radical selected from the group consisting of the phenyl radical and any.saturated aliphatic radicals, and methylene radicals cyclically connected together by three further methylene radicals to the pentamethylene ring) with an acylating and enolizing agent of the group consisting of PC15, POC13, SOC12, C6H5.SO2C1 and CH3-C6H4.SO2C1 to form an enolic ester of the type wherein Ac is a monovalent radical selected from the group consisting of -PC14, SOC1, POC12, -SOzC6Hs and SO2C6H4CH3, treating the enolic ester thus formed with a hydrazine to form a hydrazidine and treating the latter with a compound containing and yielding the nitrous acid radical under the conditions of the process.

6. The process of preparing tetrazoles which comprises treating in the presence of pyridine a non-enolized acid amide of the type:

R"II\IH (wherein R and R" respectively represent a radical selected from the group consisting of the phenyl radical and any saturated aliphatic radicals, and methylene radicals cyclically connected together by three further methylene radicals to the pentamethylene ring) with an acylating and enolizing agent of the group consisting of P015, POC13, S0012, CsH5.SO2C1 and CH3.C6H4.SO2C1 to form an enolic ester of the type wherein Ac is a monovalent radical selected from the group consisting of --PC14, -SOC1, -POC12, -SO2C6H5 and -SO2-C6H4-CH3, treating the enolic ester thus formed with a hydrazine to form a hydrazidine and treating the latter with a compound containing and yielding the nitrous acid radical under the conditions of the process.

7. The process of preparing 1-5-pentamethylene-1-2-3-4-tetrazole which comprises treating the e-leucine lactam with an acylating and enolizing agent of the group consisting of P015, P0013, SOClz, CsH5.SO2C1 and CH3.C6H4.SO2C1, treating the resulting lactim ester with a hydrazine to form a hydrazidine and treating the latter with a compound containing and. yielding the nitrous acid radical under the conditions of the process.

8. The process of preparing tetrazoles, which comprises treating with a hydrazine, at a temperature at which an intramolecular rearrangement of the ester takes place, an ester of an oxime of the type R'C=NOAc wherein Ac is a monovalent radical selected from the group consisting of --PC14, -SOC1, -POCl2, -SO2--C6H5 and SO2CsH4-CH3 and R and B" respectively represent a radical selected from the group consisting of the phenyl radical and any saturated aliphatic radicals, and methylene radicals cyclically connected together by three further methylene radicals to the pentamethylene ring, and treating the thus formed hydrazidine with a compound containing and yielding the nitrous acid radical under the conditions of the process.

9. The process of preparing tetrazoles which comprises treating with an acylating agent of the group consisting of PC15, POCls, SOC12,

the type RC=NOH wherein R and R respectively represent a radical selected from the group consisting of the phenyl radical and any saturated aliphatic radicals, and methylene radicals cyclically connected together by three further methylene radicals to the pentamethylene ring, whereby the first formed oxime ester undergoes an intramolecular rearrangement so that the ester of the enolic form of the corresponding acid amide is formed, treating the thus formed enolic ester with a hydrazine to form a hydrazidine and treating the latter with a compound containing and yielding the nitrous acid radical under the conditions of the process.

10. The process of preparing 1-5-pentamethylene-1-2-3-4-tetrazole which comprises treating cyclohexanone-oxime with an acylating agent of the group consisting of PC15, P0013, SOC12, CsI-I5SO2C1 and CH3C6H4SO2C1, treating the resulting enolic ester of the e-leucine lactam with a hydrazine to form a hydrazidine and treating the latter with a compound containing and yielding the nitrous acid radical under the conditions of the process.

11. The process of preparing I-S-pentamethylene-l-2-3-4-tetrazole which comprises treating cyclohexanone-oxime with a sulfonyl chloride of the benzene series at a temperature at which intramolecular rearrangement to the first formed sulphonic acid ester of cyolohexanone oxime to the enolic ester of e-leucine lactam takes place, treating the thus formed enolic ester with a hydrazine to form a hydrazidine and treating the latter with a compound containing and yielding the nitrous acid radical under the conditions of the process.

GEORG SCHEUING. BRUNO WALACH. 

